The long-term objective of this grant has been the development of effective therapeutic vaccines against malignant melanoma. The Project's focus is the evaluation of a living irradiated polyvalent melanoma cell vaccine (PMCV). This project has four Specific Aims: 1) We will conduct a multicenter randomized Phase III trial in AJCC Stage III melanoma to test the hypothesis that PMCV plus BCG has superior activity in prolonging disease free and overall survival when compared to placebo plus BCG as a post surgical adjuvant. 2) Determine the immune response that optimally correlates with the clinical outcome of PMCV recipients enrolled in the Phase III trial. Our goal is to develop an immune response model that can serve as a prototype for monitoring vaccine therapy in patients with melanoma. 3) Determine whether the immune response against tumor-associated antigens can be enhanced by combining PMCV immunotherapy with cytokines that are effective vaccine adjuvants for inducing tumor rejection responses in animal models, such as GMCSF and IL-12 and whether manipulation of co-stimulatory molecules on melanoma cells can enhance immmunogenicity. 4) To determine whether new tumor markers can be used to detect subclinical metastatic melanoma and quantitate the response to adjuvant therapy. We hypothesize that these new techniques will be useful in predicting the outcome of adjuvant therapy for melanoma patients who have no clinical evidence of disease following sugery.